Gab1 in livers with persistent hepatocyte apoptosis has an antiapoptotic effect and reduces chronic liver injury, fibrosis, and tumorigenesis

Abstract

Grb2-associated binder 1 (Gab1) is an adaptor protein that is important for intracellular signal transduction by receptor tyrosine kinases that are receptors for various growth factors and plays an important role in rapid liver regeneration after partial hepatectomy and during acute hepatitis. On the other hand, mild liver regeneration is induced in livers of individuals with chronic hepatitis, where hepatocyte apoptosis is persistent; however, the impact of Gab1 on such livers remains unclear. We examined the role of Gab1 in chronic hepatitis. Gab1 knockdown enhanced the decrease in cell viability and apoptosis induced by ABT-737, a Bcl-2/-xL/-w inhibitor, in BNL.CL2 cells, while cell viability and caspase activity were unchanged in the absence of ABT-737. ABT-737 treatment induced Gab1 cleavage to form p35-Gab1. p35-Gab1 was also detected in the livers of mice with hepatocyte-specific Mcl-1 knockout (KO), which causes persistent hepatocyte apoptosis. Gab1 deficiency exacerbated hepatocyte apoptosis in Mcl-1 KO mice with posttranscriptional downregulation of Bcl-XL. In BNL.CL2 cells treated with ABT-737, Gab1 knockdown posttranscriptionally suppressed Bcl-xL expression, and p35-Gab1 overexpression enhanced Bcl-xL expression. Gab1 deficiency in Mcl-1 KO mice activated STAT3 signaling in hepatocytes, increased hepatocyte proliferation, and increased the incidence of liver cancer with the exacerbation of liver fibrosis. In conclusion, Gab1 is cleaved in the presence of apoptotic stimuli and forms p35-Gab1 in hepatocytes. In chronic liver injury, the role of Gab1 in suppressing apoptosis and reducing liver damage, fibrosis, and tumorigenesis is more important than its role in liver regeneration.

The Role of ERBB Signaling Pathway-Related Genes in Kidney Renal Clear Cell Carcinoma and Establishing a Prognostic Risk Assessment Model for Patients

“…GAB1 promotes BRCA metastasis by interacting with the critical component PAR3 of the PAR complex and EMT of mammary gland tumors. In chronic liver injury, GAB1 plays an essential role in inhibiting apoptosis and reducing liver injury, fibrosis, and tumorigenesis ( Mizutani et al, 2021 ).…”

Identification of miRNA-target gene regulatory networks in liver fibrosis based on bioinformatics analysis

“…Fibroblast growth factor receptor, a major family of receptor tyrosine kinases, plays a key role in the progression and resolution of liver fibrosis by interacting with HSCs, hepatocytes and immune cells ( Seitz & Hellerbrand, 2021 ). In addition, knockdown of Gab1 , an important protein in the receptor tyrosine kinase pathway, significantly exacerbated liver fibrosis in animal models ( Mizutani et al, 2021 ). According to KEGG pathway analysis, phagosome was most highly enriched pathway, which was consistent with other studies that revealed that autophagy and LC3-associated phagocytosis were closely related to the pathogenesis of liver fibrosis ( Li et al, 2020 ; Wan et al, 2020 ).…”

The Role of GAB1 in Cancer

“…GAB1 is involved in diverse biological processes such as cell proliferation, survival, invasion and migration, cell differentiation, angiogenesis, and inflammation [ 11 , 67 , 68 , 69 , 70 ]. All these functions of GAB1 appear to be fundamental to the processes underlying malignant transformation, including tumor angiogenesis and metastasis ( Figure 3 ).…”